WO2013138964A1 - Application d'un composé d'iso-daphnétine dans la préparation de médicaments antidiabétiques - Google Patents

Application d'un composé d'iso-daphnétine dans la préparation de médicaments antidiabétiques Download PDF

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Publication number
WO2013138964A1
WO2013138964A1 PCT/CN2012/001297 CN2012001297W WO2013138964A1 WO 2013138964 A1 WO2013138964 A1 WO 2013138964A1 CN 2012001297 W CN2012001297 W CN 2012001297W WO 2013138964 A1 WO2013138964 A1 WO 2013138964A1
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WO
WIPO (PCT)
Prior art keywords
iso
daphnetin
rats
preparation
type
Prior art date
Application number
PCT/CN2012/001297
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English (en)
Chinese (zh)
Inventor
张卫东
单磊
苏娟
李慧梁
柳润辉
沈云亨
徐希科
张寿德
Original Assignee
中国人民解放军第二军医大学
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Application filed by 中国人民解放军第二军医大学 filed Critical 中国人民解放军第二军医大学
Publication of WO2013138964A1 publication Critical patent/WO2013138964A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the invention relates to drugs. Specifically, it relates to the use of iso-rhimelin compounds in the preparation of anti-diabetic drugs. Background technique
  • Oral anti-hyperglycemic drugs commonly used in clinical practice include: PPAR Y agonists, sulfonylureas that promote insulin secretion, Lenin, and biguanides.
  • the above drugs are only effective within a certain range, can not effectively control the development of diabetes, and have limited tolerance or varying degrees of adverse reactions, such as: glucose intolerance, hypoglycemia, weight gain, lactic acidosis and edema.
  • Isoflavin is from the Daphne plant of Phylaceae (Daphne), Phnom Penh (Daphne)
  • Source s Phnom Penh Daphne odora Thunb. var. marginata There are about 44 species of Chinese genus, which are rich in resources. Its roots, stems, leaves and flowers can be used as medicines. It is sweet and non-toxic. It has the functions of clearing heat and reducing fire, reducing inflammation, swelling, promoting blood circulation, and relieving pain. According to the "Chinese Medicine Dictionary", Ruixiang leaves can cure sore and wind pain; flowers can cure sore and swollen teeth; roots can cure snake bites, bruises and other diseases. In recent years, there have been many studies on the pharmacological activities of the extracts of Rhizoma rugulosa.
  • Jinbian Ruixiang is small. The cellular immunity, non-specific immunity and erythrocyte immune function of the mouse are promoted. The inventors conducted a systematic chemical composition study on Jinbian Ruixiang, and found that the chemical component of ruthenium has a good anti-diabetic effect. So far, there has been no report on the anti-diabetic effect of Phnom Penh. Summary of the invention
  • the technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies, to study the new use of the sirolimus, and to design an effective anti-diabetic drug.
  • the present invention provides the use of isolisin in the preparation of an antidiabetic drug.
  • the ruthenium sulphate provided by the invention is obtained by the following method - the medicinal material of Phnom Penh is extracted by 75% ethanol, and the extract is concentrated under reduced pressure to obtain an extract, and the obtained crude extract is extracted with petroleum ether, chloroform and ethyl acetate respectively. , the ethyl acetate fraction was subjected to repeated silica gel H (200 to 300 mesh) column chromatography, chloroform: acetone (10: 1-1: 1), chloroform: methanol (50: 1-1: 1) gradient elution, Sephadex LH -20 column chromatography and reverse phase silica gel (Merck), the compound was obtained.
  • the invention adopts a high-sugar and high-fat diet combined with a low-dose streptozotocin (STZ) type 2 diabetic rat model, which is in line with the pathogenesis of human common type 2 diabetes, and is beneficial for the discovery of therapeutic drugs for type 2 diabetes.
  • STZ streptozotocin
  • the results of the experiment showed that the blood glucose level and glucagon level of type 2 diabetic rats decreased significantly after treatment with iso-rhimexin (P ⁇ 0.01), while insulin increased significantly, and there was no significant difference in blood glucose between the groups. (P>0.05). Therefore, isorubicin can be used to prepare an anti-diabetic drug.
  • the oral hypoglycemic agent metformin was used as a positive control, and the results showed that the isoxanthin and the positive drug metformin have considerable activity and have the functions of protecting and repairing islet cells.
  • the pharmaceutical composition of the present invention comprises a pharmaceutical composition comprising isosericin as an active ingredient and a pharmaceutically acceptable carrier.
  • the invention has good anti-diabetic effect, and has the functions of protecting and repairing islet cells.
  • the active ingredient isorubicin is derived from an extract of natural products, and is superior to chemical drugs and hypoglycemic agents in side effects and the like. Large clinical application value. detailed description
  • Phnom Penh fragrant herbs (commercially available) were pulverized and extracted with 150L 75% ethanol. The extract was concentrated under reduced pressure to obtain 8L extract. After the extract was diluted with 10L of water, 100L petroleum ether and 100L chloroform were used. 100 L of ethyl acetate was extracted, and the ethyl acetate fraction was collected and weighed to 125 g. The ethyl acetate fraction was subjected to two times of silica gel H (200 to 300 mesh) column chromatography, chloroform:acetone (10 : 1 to 1 : 1), chloroform. : Methanol (50: 1 ⁇ 1: 1) gradient elution, Sephadex LH-20 column chromatography and reversed-phase silica gel (Merck), to obtain 108 mg of the compound isotretin.
  • Example 2 The isoericin prepared in Example 1 was used in the following experiment.
  • Example 2 The isoericin prepared in Example 1 was used in the following experiment.
  • Material Irradix is prepared by the preparation of Example 1.
  • Model establishment 60 healthy Wi star rats, 10 randomly selected as normal control group (I), fed with conventional diet. 50 rats of the model were replicated. After 8 weeks of high-calorie diet, a small dose of 35 mg I kg STZ was intraperitoneally injected (STZ was diluted to 1 with 0.1 mol of sodium citrate-sodium citrate solution (pH 4.0). % of the solution), 72 h after the determination of fasting blood glucose stable at 11 mmol I blood glucose 29 ramol IL for the type 2 diabetes model required for this trial.
  • the diabetic model rats were randomly divided into 5 groups according to the blood glucose level, and 10 rats in each group were: normal control group (1), diabetes model group (11), low-dose group of different components (111), medium dose Group (IV), high dose group (V) (dissolved in a solution of 0.5% sodium carboxymethylcellulose (CMC-Na)) and metformin positive control (VI). 5% ⁇ carboxymethylcellulose was administered to groups I and II, respectively.
  • the above experiments show that the isoforms of the present invention are related to the type 2 sugar established by streptozotocin (STZ) combined with high fat diet.
  • STZ streptozotocin
  • the urinary rat model has better glycemic inhibitory activity and is equivalent to the positive drug metformin.
  • the changes of serum insulin and glucagon levels in this experiment indicate that isorubicin has the function of protecting and repairing islet cells, and can reduce the level of glucagon in serum and inhibit the possible pathogenesis of diabetes. . Therefore, isorubicin can be developed as a drug for treating diabetes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

La présente invention concerne une application d'un composé d'iso-daphnétine dans la préparation de médicaments antidiabétiques. La formule structurale de l'iso-daphnétine est décrite ci-après. Dans la présente invention, un fourrage riche en sucre et riche en graisse combiné à une faible dose de streptozotochine (STZ) est appliqué pour établir un modèle de rat atteint du diabète de type 2. Des rats adultes SD mâles sont nourris avec un fourrage riche en sucre et riche en graisse pendant un mois pour entraîner une insulinorésistance et se voient injecter une faible dose de STZ (25 mg/kg) dans la cavité abdominale pour établir le modèle de rat atteint du diabète de type 2. Ensuite, un médicament est injecté dans la cavité abdominale. La glycémie, l'insulinémie, le glucagon, l'état métallique, le poids, la consommation d'eau, la consommation d'aliments, et ainsi de suite, des rats sont utilisés en tant qu'indices de test. Un résultat expérimental démontre qu'après un traitement avec de l'iso-daphnétine, les valeurs de glycémie et les insulinémies des rats atteints de diabète de type 2 ont réduit considérablement (p < 0,01), et, lorsque l'insuline a accrue considérablement, les glycémies des groupes de dosage ne sont pas fortement différentes (p > 0,05). Par conséquent, l'iso-daphnétine peut être utilisée pour la préparation de médicaments antidiabétiques. Selon la présente invention, le médicament est une composition pharmaceutique formée par l'isodaphnétine en tant que principe actif et excipient médicinal.
PCT/CN2012/001297 2012-03-19 2012-09-24 Application d'un composé d'iso-daphnétine dans la préparation de médicaments antidiabétiques WO2013138964A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210073964XA CN102626407A (zh) 2012-03-19 2012-03-19 异瑞香新素化合物在制备抗糖尿病药物中的应用
CN201210073964.X 2012-03-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111925349A (zh) * 2020-09-03 2020-11-13 上海海洋大学 抑制剂瑞香素衍生物及其应用和药物组合物
CN114225012A (zh) * 2021-12-16 2022-03-25 浙江湃肽生物有限公司 一种测定索玛鲁肽生物活性的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102626407A (zh) * 2012-03-19 2012-08-08 中国人民解放军第二军医大学 异瑞香新素化合物在制备抗糖尿病药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102626407A (zh) * 2012-03-19 2012-08-08 中国人民解放军第二军医大学 异瑞香新素化合物在制备抗糖尿病药物中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102626407A (zh) * 2012-03-19 2012-08-08 中国人民解放军第二军医大学 异瑞香新素化合物在制备抗糖尿病药物中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
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SHOUDE ZHANG ET AL.: "Fast and effective identification of the bioactive compounds and their targets from medicinal plants via computational chemical biology approach.", MED. CHEM. COMMUN., vol. 2, 13 May 2011 (2011-05-13), pages 471 - 477 *
XU WEN-ZHENG ET AL.: "Chemical constituents of daphne pedunculata.", CHINESE JOURNAL OF NATURAL MEDICINES., vol. 6, no. 1, January 2008 (2008-01-01), pages 30 - 32 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111925349A (zh) * 2020-09-03 2020-11-13 上海海洋大学 抑制剂瑞香素衍生物及其应用和药物组合物
CN111925349B (zh) * 2020-09-03 2022-08-26 上海海洋大学 抑制剂瑞香素衍生物及其应用和药物组合物
CN114225012A (zh) * 2021-12-16 2022-03-25 浙江湃肽生物有限公司 一种测定索玛鲁肽生物活性的方法
CN114225012B (zh) * 2021-12-16 2022-10-25 浙江湃肽生物股份有限公司 一种测定索玛鲁肽生物活性的方法

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